Pentachlorophenol has been used as an herbicide, algicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. Pentachlorophenol was nominated by the National Cancer Institute for carcinogenicity testing based on its widespread use as a wood preservative, potential for entering the environment (pentachlorophenol residues have been found worldwide in soil, water, and air samples; in food products; and in human and animal tissues and body fluids), and likelihood of bioaccumulation in the environment (pentachlorophenol is persistent in soil, having a half-life of up to 5 years). Technical Report No. 349 contains the results of the 2-year studies of pentachlorophenol performed by the NTP with B6C3F1 mice.

Male and female F344/N rats were exposed to pentachlorophenol (approximately 99% pure) in feed for 28 days or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow cells.

28-DAY STUDY IN RATS

Groups of 10 male and 10 female F344/N rats were given 0, 200, 400, 800, 1,600, or 3,200 ppm pentachlorophenol, equivalent to average daily doses of approximately 20, 40, 75, 150, or 270 mg pentachlorophenol/kg body weight to males and females in feed for 28 days. With the exception of one male and two females exposed to 3,200 ppm, all rats survived until the end of the study. The final mean body weights and body weight gains of male rats exposed to 1,600 or 3,200 ppm and female rats exposed to 400, 800, 1,600, or 3,200 ppm were significantly less than those of the controls; rats exposed to 3,200 ppm lost weight during the study. Feed consumption by 3,200 ppm males was less than that by the control group throughout the study. The absolute and relative liver weights of 400, 800, and 1,600 ppm males and all exposed groups of females were significantly greater than those of the controls. Compared to the control groups, the incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3,200 ppm groups were increased.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were fed diets containing 200, 400, or 600 ppm pentachlorophenol (equivalent to average daily doses of approximately 10, 20, and 30 mg/kg) for 105 weeks. Stop-exposure groups of 60 male and 60 female rats received 1,000 ppm (equivalent to 60 mg/kg) in feed for 52 weeks, after which animals received undosed feed for the remainder of the 2-year study; 10 male and 10 female control and 1,000 ppm rats were evaluated at 7 months.

Survival, Body Weights,and Feed Consumption
In the 2-year study, survival of 600 and 1,000 ppm males was greater than that of the controls. Mean body weights of 400 and 600 ppm males and females were generally less than those of controls. When exposure to pentachlorophenol was discontinued at week 52, mean body weights of 1,000 ppm males and females were 17% and 22% lower than those of the respective controls; however, by the end of week 87, the mean body weights were similar to those of the controls. Generally, feed consumption by exposed groups was similar to that by the controls.

Pathology Findings
At 2 years, the incidence of malignant mesothelioma originating from the tunica vaginalis was significantly greater in 1,000 ppm males than in the controls, and the incidence exceeded the historical control range. Nasal squamous cell carcinomas were present in one control male, three 200 ppm males, one 400 ppm male, and five 1,000 ppm males at 2 years, and the incidence in 1,000 ppm males exceeded the historical control range. At the 7-month interim evaluation, the incidences of centrilobular hepatocyte hypertrophy in 1,000 ppm males and females and hepatocyte cytoplasmic vacuolization in 1,000 ppm males was significantly greater than those in the controls. At 2 years, the incidences of several nonneoplastic liver lesions including hepatodiaphragmatic nodules and hepatocyte cystic degeneration in all exposed groups of males and basophilic foci in 1,000 ppm males were increased compared to the controls.

GENETIC TOXICOLOGY

Pentachlorophenol (91.6% pure) was tested in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 at doses up to 30 µg/plate with and without induced rat or hamster liver S9; no significant increases in the number of revertant colonies were observed in any of the strain/activation combinations. When tested for cytogenetic effects in cultured Chinese hamster ovary cells, pentachlorophenol was weakly positive for induction of sister chromatid exchanges and chromosomal aberrations. In the sister chromatid exchange test, a weakly positive response was observed within a concentration range of 3 to 30 µg/mL in the absence of S9; with S9, no induction of sister chromatid exchanges was noted. In the chromosomal aberrations test, pentachlorophenol was negative without S9 but induced small but significant increases in the frequency of aberrant cells in the presence of S9 at doses of 80 and 100 µg/mL. In contrast to the positive in vitro results in the test for induction of chromosomal aberrations, no increase in the frequency of micronucleated erythrocytes was noted in bone marrow of male rats or mice administered pentachlorophenol by intraperitoneal injection three times at 24 hour intervals. The highest dose administered to rats (75 mg/kg) and mice (150 mg/kg) was lethal.

CONCLUSIONS

Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of pentachlorophenol in male or female F344/N rats fed diets containing 200, 400, or 600 ppm. There was some evidence of carcinogenic activity of pentachlorophenol in male F344/N rats given feed containing 1,000 ppm for 1 year followed by control feed for 1 year (stop-exposure study), based on increased incidences of mesothelioma and nasal squamous cell carcinoma. There wasno evidence of carcinogenic activity of pentachlorophenol in female rats given feed containing 1,000 ppm for 1 year and maintained on control feed for 1 year.

Stop-exposure males and females recovered from a transitory reduction in body weight gain by the end of the 2-year study, and males had increased survival compared to the controls.